The object of the present invention is peptides that can be recognized by antibodies in biological fluids, in particular serums in patients or animals stricken with auto-immune diseases such as systemic Lupus Erythematosus or diseases of the nervous systems such as Alzheimer's or Parkinson's diseases.
The invention also concerns applications of these peptides and compositions containing them in in vitro diagnoses in man of the potentiality of certain auto-immune or nervous-system diseases, as well as their use in diagnostic kits.
The invention further concerns the application of these peptides in the production of immunogenic compositions and of vaccines used against these diseases.
Finally, the invention concerns antibodies that can be induced in vivo by these immunogenic peptides and compositions which contain them used for in vitro diagnosis in patients stricken with auto-immune or nervous-system diseases, as well as the manufacture of medications used against these diseases.
Stress proteins are involved in a variety of diseases, such as non-viral infections and certain auto-immune diseases. Thus, S. Muller et al. (Proc. Natl. Acad. Sci., USA 85:8176, 1988) have described ubiquitine, a thermal-shock protein containing 76 amino acid residues which is present in all eukaryote cells as a principal antigenic target of Systemic Lupus Erythematosus. V. Manetto et al. have shown (Proc. Natl. Acad. Sci., USA 85:4501, 1988), that ubiquitine is implicated in diseases of the nervous system, such as Alzheimer's and Parkinson's diseases. B. S. Polla (Immunol. Today, 9:134, 1988) has demonstrated that thermal shock proteins may play a central role in all cases of inflammation in which a rise in temperature is a significant clinical sign.
It is accepted today that ubiquitine may be present in cells both in the free state and united with a large number of proteins of the nucleus, the cytoplasm, or the membrane, or may also be linked to the network of microtubules.
The conjugates of ubiquitine of the cytosol are known to be selective mediators of the breakdown of damaged or abnormal proteins.
In the nucleus, the role of the conjugates of ubiquitine with the H2A and H2B histones remains poorly understood. The formation of these conjugates is a product of a selective, reversible histone modification, which occurs most notably in the actively transcribed areas of the chromatin and which may be involved in the relaxation of the chromatin. Ubiquitine may also indirectly modulate the structure of the chromatin, by stimulating the activity of the deacetylase histone enzyme. An article by M. Rechsteiner (Ann. Rev. Cell. Biol., 3:1, 1987) states that conjugates of ubiquitine with the histones of the nucleus break down more slowly than those of ubiquitine of the cytosol.
H. Busch et al. (Molec. Cell. biol., 3:1, 1981) and A. W. Thorne et al. (EMBO J., 6:1005, 1987) have described the fact that, in the nucleus, ubiquitine is enzymatically conjugated with histones by means of a peptide bond between the group .alpha.-COOH of the C-terminal glycine in position 76 of the ubiquitine and the group--NH2 of the lateral lysine chain in position 119 in the H2A histone and in position 120 in the H2B histone, thus forming branched molecules.
In mammal cells, the H2A and H2B histones conjugated with ubiquitine are present in the proportions of 10% and 1%, respectively.
S. Muller et al. have described (Proc. Natl. Acad. Sci., USA 85:8176, 1988) the presence, in serums of patients stricken with Systemic Lupus Erythematosus, of antibodies capable of reacting in an immuno-enzymatic ELISA-type test with ubiquitine and with a synthetic fragment corresponding to the residues of amino acids 22 to 45 of said ubiquitine.